Inclusion body myositis (IBM) is the most common muscle disease in persons over 50 years of age. Although the cause of this disease remains to be determined, surprisingly it has recently been observed that many of the biochemical features that occur in brains afflicted with AIzheimer's disease also occur in IBM. The Alzheimer's disease brain is characterized by diffuse and neuritic plaques, the hallmark structures of this insidious disease. The principal constituent of these plaques is a small peptide called beta-amyloid. Various histochemical and immunological reagents have been used to show that Beta-amyloid deposits accumulate in affected muscle fibers in IBM. Consequently, IBM represents the first disease, other than those disorders related to Alzheimer's disease such as Down syndrome and vascular dementia, where pathological accumulation of the Beta- amyloid peptide occurs outside the central nervous system. Notably, the accumulation of Beta-amyloid appears to be a specific component of IBM since this peptide is not present in other muscle disorders. This finding is significant and suggests a pathophysiological role for Beta-amyloid in this common, age-related myopathy. The observation that Beta-amyloid accumulates in inclusion body myositis represents an important opportunity to study the role that this peptide plays in this muscular disorder. In this application, we propose to investigate the pathophysiological role of Beta-amyloid accumulation in skeletal muscle tissue by deriving transgenic mice that selectively overproduce this peptide. The muscle creatine kinase promoter, which has been used by other investigators to direct expression to skeletal muscle of transgenic mice, will be used to specifically target transgenes to these tissues. Two sets of transgenic mice will be derived. The first will express only the Beta-amyloid peptide and will test the hypothesis that Beta-amyloid accumulation in muscle leads to pathological changes resembling IBM and provide insights into the pathophysiological role of this peptide in muscle. Another transgenic mouse model will also be derived in which the Beta-amyloid precursor protein, the molecule from which Beta-amyloid is derived, will be overproduced in muscle; these mice will allow us to test the hypothesis that increased expression of the precursor molecule leads to unmanageable levels of Beta-amyloid. Not only would such animal models be useful for studying an age-related muscle disease like IBM, but they may also provide relevant insights into the pathophysiological role these proteins play in Alzheimer's disease as well.